3Q3T

Alkyl Amine Renin Inhibitors: Filling S1 from S3

Summary for 3Q3T

• Entry DOI: 10.2210/pdb3q3t/pdb
• Related: 3GW5 3KM4 3Q4B 3Q5H
• Descriptor: Renin, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, [(1S,3R,4S)-3-amino-4-hydroxycyclopentyl]{(3R)-3-[(1S)-1-(biphenyl-2-yl)-1-hydroxy-5-methoxypentyl]piperidin-1-yl}methanone, ... (6 entities in total)
• Functional Keywords: aspartate protease, hypertension, renin inhibitors, glycoprotein, zymogen, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P00797
• Total number of polymer chains: 2
• Total formula weight: 76325.09

Authors

Wu, Z.,McKeever, B. (deposition date: 2010-12-22, release date: 2011-08-03, Last modification date: 2024-10-30)

Primary citation

Yuan, J.,Simpson, R.D.,Zhao, W.,Tice, C.M.,Xu, Z.,Cacatian, S.,Jia, L.,Flaherty, P.T.,Guo, J.,Ishchenko, A.,Wu, Z.,McKeever, B.M.,Scott, B.B.,Bukhtiyarov, Y.,Berbaum, J.,Panemangalore, R.,Bentley, R.,Doe, C.P.,Harrison, R.K.,McGeehan, G.M.,Singh, S.B.,Dillard, L.W.,Baldwin, J.J.,Claremon, D.A.
Biphenyl/diphenyl ether renin inhibitors: Filling the S1 pocket of renin via the S3 pocket.
Bioorg.Med.Chem.Lett., 21:4836-4843, 2011

PubMed Abstract: Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the presence of human plasma, selectivity against CYP3A4 inhibition and improved rat oral bioavailability led to the identification of 8d which demonstrated antihypertensive efficacy in a transgenic rat model of human hypertension.

PubMed: 21741239
DOI: 10.1016/j.bmcl.2011.06.043

Experimental method

X-RAY DIFFRACTION (2.6 Å)